classical toxicology rusyniak - acmt · • cox1&2 inhibition! fenamates! acetic acids!...
TRANSCRIPT
![Page 2: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/2.jpg)
You know this already
• APAP • ASA • NSAIDS
• Methylxanthines (Theophylline, Theobromine, Caffeine) • CO and HBO
• Oldies and Goodies (Placidyl, Quaaludes)
![Page 3: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/3.jpg)
APAP Hx
• The most widely used analgesic in the US
• Central COX2 Inhibition
• Released in 1955 as Tylenol elixir for children
• Metabolite of phenacetin
• 2011 FDA asks to limit acetaminophen in combo products
• 1982 seven people died from deliberate cyanide contamination
![Page 4: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/4.jpg)
![Page 5: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/5.jpg)
Phenacetin/Acetaminophen
![Page 6: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/6.jpg)
Renal Papillary Necrosis
![Page 7: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/7.jpg)
Unchanged in Urine
40-65% Glucuronidation
Sulfation 20-45%
Phase II
5%
CYP2E1, CYP3A4 CYP2E1, 1A2, 3A4
NAPQI
Mercapturic acid (nontoxic)
Glutathione
Necrosis
Biotransformation APAP
Phase I
![Page 8: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/8.jpg)
NAPQI
• Highly reactive • Binds cellular proteins • Necrosis • Liver and kidneys contain the
majority of p450 • Injury occurs when glutathione
<30-50% of baseline
N
O
O
![Page 9: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/9.jpg)
Central
Middle
Peripheral
Central
Middle
Peripheral
HA
PV BD CV
CV
Why centrilobular?
• Increased p450 • Decreased glutathione
![Page 10: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/10.jpg)
Phases of Tox
• Phase I (0.5-24 hour) – nausea, anorexia, malaise
• Phase II (24-72 hour) – “quiescent” phase, LFT’s rise, RUQ pain
• Phase III (72-96 hour) – Hepatic necrosis, jaundice, encephalopathy
• Phase IV (4 days–2 weeks) - recovery
![Page 11: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/11.jpg)
HN
O
HS
O
NH
NH2
HO
O OH
O
O
OH
HN
OHS
Glutathione
N-acetylcysteine
NAC
![Page 12: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/12.jpg)
NAC Dosing • Oral
• 140 mg/kg load
• 70 mg/kg q 4 h x 72h
• IV
• 150 mg/kg load over 60 min
• 50 mg/kg over 4 hrs
• 100 mg/kg over 16 hrs
![Page 13: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/13.jpg)
Keays R, Harrison PM, Wendon JA et al. Intravenous acetylcysteine in paractamol induced fulminant hepatic failure: A prospective controlled trial. BMJ. 1991, 303:1026-9.
50 APAP-Induced Hepatic Failure w/Poor Prognosis Presented 55 h (mean)
Survival 48% Cerebral Edema 40% Inotropic Support 48%
Survival 20% Cerebral Edema 68% Inotropic Support 80%
NAC Placebo
NAC works late
![Page 14: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/14.jpg)
Prognosis
• Treatment within 10 hrs – Mortality <1%
Kings College Criteria
• Ph < 7.30 = Mortality ~80%*
• Encephalopathy + coagulopathic (INR>6.5) + Renal Failure (Cr>3.3) = Mortality ~80%*
![Page 15: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/15.jpg)
Acetaminophen and the Fetus
• APAP crosses the placenta
• Important cause of fetal demise
• Prior to 16 weeks fetus has low p450 activity (protective)
• N-acetylcysteine crosses the placenta
![Page 16: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/16.jpg)
Anaphalactoid reactions
• Dose dependent
• Cutaneous (most common)
• Transient flushing, urticaria, pruritus, edema
• Systemic (rare)
• Hypotension, wheezing
• Highest risk group brittle asthmatics
![Page 17: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/17.jpg)
Uncommon APAP
• Altered mental status & metabolic acidosis – 5—Oxoproline
• Decreased glutathione synthetase activity
• Hemolytic Anemia – G6PD deficiency
• Isolated Renal Failure
• NAC – increases INR
![Page 18: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/18.jpg)
Aspirin • Derived from Willow Bark
• Inhibits cyclooxygenase
http://chemistry.gravitywaves.com/CHE452/images/Aspirin.gif
![Page 19: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/19.jpg)
Mechanism of Action
Increase renal blood flow
Platelet aggregation
Pain sensation
Inflammation
Fever
Increase GI mucous production and decrease acid secretion
Decreased Pain Decreased Fever Decreased inflammation Decreased clotting (MI) Bleeding disorders GI ulcers Renal Failure
Prostaglandins
![Page 20: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/20.jpg)
Oxidative Phosphorylation
NADH
Complex I
e-
Complex IV
H+ H+ H+
H2O
ATPase
ATP
Ψ
Complex III
Complex IV
F1/Fo ATPase
½ O2 + 2H+
NAD+
Q
Cyt. C
![Page 21: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/21.jpg)
Uncoupling
NADH
Complex I
e-
Complex IV
H+ H+ H+
H2O
ATPase
ATP
Ψ
Complex III
Complex IV
F1/Fo ATPase
ASA H+
ASA H+
ASA H+ ½ O2 + 2H+
NAD+
Q
Cyt. C
![Page 22: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/22.jpg)
Michaelis-Menten Kinetics
For more pharmacokine0cs go to h4p://www.boomer.org/
![Page 23: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/23.jpg)
Symptoms ASA concentrations 150 – Death/dL
100 – CNS, CV collapse, Non cardiogenic pulmonary edema
75 – Lethargy, worsening acidosis, fever
50 – Tinnitus, hyperventilation, metabolic acidosis
10 mg/dl – Antiplatelet, antipyretic
30 mg/dl – Anti-inflammatory, mild tinnitus, nausea
![Page 24: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/24.jpg)
Chronic Salicylism
• Elderly • chronic pain
• More likely to present with fever, altered mental status, and pulmonary edema
• Poor correlation between levels and toxicity
![Page 25: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/25.jpg)
Unrecognized Adult Salicylate Intoxication ���Anderson R, et al Annals of Internal Medicine 1976; 85:745
73 ASA Poisoned Adults
Group I N = 53 Inten0onal Inges0on Mean Age 32 Mortality 2%
Group II N= 20 Uninten0onal Mean age 53.4 Delayed Diagnosis 6-‐72 h Mortality 25%
![Page 26: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/26.jpg)
Treatment • Alkalinization
• Increases urinary elimination/decrease tissue levels
• Elevated level (>35 mg/dL)
• Symptomatic
• Metabolic acidosis
• Renal clearance increased 20 fold at urine pH 8.0 vs pH 5.0
![Page 27: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/27.jpg)
Rationale for alkalinization
Acidic condi0ons
Alkaline condi0ons
Salicylate pKa = 3.0 so it tends toward a HA (non-ionized) form under acidic conditions and in A-(ionized) form in alkaline conditions
HA
HA
HA
H+ + A-‐
H+ + A-‐
H+ + A-‐
![Page 28: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/28.jpg)
Ion trapping
Renal tubular cell (pH 7.4) Urine pH 8.0
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
HA H+
H+
H+ Buffered in alkaline environment
Unable to cross back into body
![Page 29: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/29.jpg)
Dialysis
• Level > 80 mg/dL • Pulmonary edema • Neurologic deficits • Hemodynamic instability • Persistent acidosis
![Page 30: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/30.jpg)
Uncommon ASA
• Coagulopathy
• Non-cardiogenic pulmonary edema
• Hyperglycemia followed by hypoglycemia
• Rhabdomyolysis
• Seizures
![Page 31: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/31.jpg)
NSAIDS
• COX1&2 inhibition
Fenamates Acetic acids Propionic acids Oxicams COX-2 spec Mefenamic acid Indomethacin Ibuprofen Peroxicam Celecoxib
Ketorolac Naproxen Diclofenac Ketoprofen
![Page 32: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/32.jpg)
Mechanism of Action Cell membrane Phospholipids
Arachadonic acid
Prostaglandins
Cyclo-oxygenase NSAID-reversible ASA-irreversible
Vasodilatation, erythema, edema, pain, fever, smooth muscle contraction, GI cytoprotection
![Page 33: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/33.jpg)
Effect of Renal PG’s • Dilate afferent renal arterioles
• Increase GFR in low flow states • Release renin= aldosterone release
• K+ secretion into DT • Inhibit ADH effects on DT
• H2O diuresis • Inhibit Na+ resorption in LOH
• Natriuresis
![Page 34: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/34.jpg)
General Toxicity
• GI (N/V) • Metabolic acidosis • CNS depression • Renal
• Dehydration + NSAID = Renal insufficiency • Hyperkalemia
![Page 35: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/35.jpg)
NSAID Unique Toxicity
• Seizures – Proprionic acids, mefenamic acid
• Prolongation of PT – Proprionic acids, mefanamic, indomethacin
• Hepatitis – mefanamic acid, naproxen
![Page 36: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/36.jpg)
Carbon Monoxide
• Number one cause of poisoning deaths
• Produced during incomplete combustion
• Endogenous (heme breakdown)
• 2nd messenger increases cGMP
![Page 37: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/37.jpg)
CO physiology
• CO binds tightly with iron complex of Hemoglobin
• Binds similar to O2
• Dissociates 200 – 300 less readily
• Decrease arterial O2 content
![Page 38: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/38.jpg)
Left – Leaves O2
Right – Releases O2
![Page 39: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/39.jpg)
Clinical Effects Severity Neurologic Cardiac
Headache (releases NO)
Mild Nausea/Vomiting
Dizziness Tachycardia
Cognitive dysfunction Chest Pain
Somnolence Dyspnea/Tachypnea
Moderate Ataxia Tachycardia
Seizures Chest Pain/MI
Coma Arrhythmias
Severe CVA Hypotension
Death Cardiac collapse
![Page 40: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/40.jpg)
Basal Ganglia Infarcts
Coric V, J Neurol Neurosurg Psychiatry. Aug 1998; 65(2): 245–247.
![Page 41: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/41.jpg)
BG Infarctions • Watershed area few anastomoses
• Song et al, Acta Neuropathologica, 1983:232-8
• Predicts worse outcome
• Sawada et al, Lancet, April 12, 1980
• Parkinsonian syndrome
• Klawans et al, Arch Neurol,1982, 39:302-304
![Page 42: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/42.jpg)
Delayed Neurologic Sequelae
![Page 43: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/43.jpg)
Delayed Neurologic Sequelae
• 3%-20% of CO poisoned patients • Older age
• Hypotension
• Coma
• Loss of consciousness
![Page 44: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/44.jpg)
Delayed Neurologic Sequelae • 4 days to 4 weeks after acute injury
• Cognitive and emotional deterioration
• Frontal release signs
• Diffuse demyelination of white matter
![Page 45: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/45.jpg)
Autoimmune?
• Regional hypoperfusion
• Free radical formation
• Oxygen Free Radicals
• Changes in Myelin Basic Protein
• Immune Response
![Page 46: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/46.jpg)
HBO for CO
• Hyperoxygenation
• Increased dissolved O2 (Boyle’s Law)
• Increased Elimination
• T1/2 from 300 min (1ATA/21%) – 20 min (2.8 ATA/100%)
• Vasoconstriction/ò Cerebral edema
• Inhibits Leukocyte activation
![Page 47: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/47.jpg)
CO and pregnancy
• Fetal hemoglobin
• Elimination takes 3.5 times longer
• Increases risk of
• Fetal demise
• Lower birth weights
• No clear syndrome of congenital defects
![Page 48: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/48.jpg)
Prolonged CO levels
![Page 49: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/49.jpg)
Methylxanthines
Theophylline Caffeine Theobromine
![Page 50: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/50.jpg)
Methylxanthines • Phosphodiesterase inhibitors
• Asthma, Neonatal apnea, Waking me up in the am
• Increase circulating catecholamines
• Elimination half-life ~8h (CYP1A2)
• Decreased by cimetidine, macrolides, antifungals
• Increased by smoking
• Enterohepatic circulation
• Multidose activated charcoal
![Page 51: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/51.jpg)
Symptoms
• Refractory vomiting • Central
• Gastric Acid secretion
• Hypokalemia • Hypotension
• Beta-2 dilation • Ventricular fibrillation
GI
CV
![Page 52: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/52.jpg)
Seizures • Decrease GABA
• Depress plasma pyridoxal 5'-phosphate
• Adenosine receptor (A1) antagonists
• Refractory
• Mortality 30%
• Acute Treatment: Benzo, Barbs, Pyridoxine
• Prophylaxis: (levels approach 100 mg/l)
• Phenobarb
![Page 53: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/53.jpg)
Treatment
• MDAC
• Phenobarb prophylaxis
• Beta Blocker (?)
• PPI (refractory vomiting)
• Hemodialysis
• Levels ~100 mg/l Gal et al, 1984; JAMA. 251(23)
T1/2 =17 h
T1/2 =6 h
![Page 54: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/54.jpg)
Levels
Acute 100 mg/l threshold for action
Olson et al, 1985; Ann EM, 3, 386-394
![Page 55: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/55.jpg)
The S#*T that killed Elvis • Rx Drugs
• Morphine & Demerol • Methaqualone • Multiple Barbiturates • Valium • Placidyl • Ethinamate • Chlorpheniramine
Dr. Nichopoulus – Rx for 5,300 pills between Jan – Aug 1977
![Page 56: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/56.jpg)
Ethchlorvynol
• Sedative-Hypnotic
• Chlorinated Tertiary alcohol
• Short duration of action
• Hepatically metabolized
• CNS and Cardiac depression
• Noncardiogenic Pulmonary Edema
![Page 57: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/57.jpg)
Ethinamate • Valmid ® • Short acting sedative hypnotic
• Mechanism of action: unknown • CNS depression & coma • Death from respiratory arrest
![Page 58: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/58.jpg)
Methaqualone • Ludes, Lemmons (714)
• Sedative-hypnotic
• CNS depression
• Respiratory arrest
![Page 59: Classical Toxicology Rusyniak - ACMT · • COX1&2 inhibition! Fenamates! Acetic acids! Propionic acids! Oxicams! COX-2 spec! Mefenamic acid! Indomethacin! Ibuprofen ! ... • Rx](https://reader031.vdocuments.us/reader031/viewer/2022022507/5ac5de427f8b9a220b8d8fa3/html5/thumbnails/59.jpg)